2. Academic Validation
  3. New mechanistic understanding of FXR agonist Vonafexor: inducing sublethal damage of HBV-positive liver cancer cells via promoting anti-tumor immunity

New mechanistic understanding of FXR agonist Vonafexor: inducing sublethal damage of HBV-positive liver cancer cells via promoting anti-tumor immunity

  • Br J Cancer. 2025 Sep;133(5):697-708. doi: 10.1038/s41416-025-03089-z.
Banglun Pan # 1,  Siyan Chen # 2,  Zhu Zhang # 1,  Dongjie Ye 1,  Xiaoxia Zhang 1,  Yuxin Yao 1,  Yue Luo 1,  Hao Wu 1,  Xiaoqian Wang 1,  Nanhong Tang 3 4 5 6
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
  • 2 Department of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, China.
  • 3 Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China. fztnh@fjmu.edu.cn.
  • 4 Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China. fztnh@fjmu.edu.cn.
  • 5 Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou, China. fztnh@fjmu.edu.cn.
  • 6 Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China. fztnh@fjmu.edu.cn.
  • # Contributed equally.
PMID: 40588513 DOI: 10.1038/s41416-025-03089-z
Abstract

Background: In hepatitis B virus (HBV)-infected patients, there's an increase in exhausted T and NK cells, as well as myeloid-derived suppressor cells (MDSCs) in liver, suggesting that boosting immune responses is beneficial. While Vonafexor inhibits HBV transcriptional activity, its effects on the immune microenvironment of HBV-positive hepatocellular carcinoma (HCC) and the mechanisms of immune clearance of these infected cells are not well understood.

Methods: In this study, tumor tissues from HBV-positive HCC patients were orthotopically transplanted into the livers of Hu-SRC mice to replicate the tumor microenvironment of the patients. Immunofluorescence, flow cytometry, immunoblotting, and RT-qPCR were used to investigate the mechanism by which Vonafexor promoted sublethal damage of virus-positive HCC cells.

Results: We found that the therapeutic efficacy of Vonafexor in inducing sublethal damage of HBV-positive HCC cells was attributed to its ability to inhibit CD36-mediated free fatty acid intake and enhance GZMB expression in T and NK cells. This effect was mediated through the downregulation of hepatitis B e antigen, which inhibited mitochondrial ROS, thereby augmenting their cytotoxicity via cGAS-STING-NF-κB signaling. Additionally, Vonafexor blocked c-Rel nuclear entry in MDSCs, reducing their infiltration.

Conclusions: Our study indicated that Vonafexor showed potential as an immunotherapy for HBV-positive HCC.

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